Urazoles



Warren J. Close and Daniel A. Dunnigan, w uke an, 11]., QSSIQII'OIS to Abbott Laboratories, North Chicago, 111., a corporation of Illinois No Drawing. Filed June 25, 1958, Ser. No. 744,354 8 Claims. (Cl. 260-308) invention relates to novel derivatives of fiverernhered heterocycles. More particularly" this invennon relates to novel derivatives of urazole characterized by the followin structural fin'fillil'at by the electroshock technique, by Metrazol and by psychomotor shock and are therefore useful as anticonvulsants.

The novel disubstituted urazole derivatives of this invention can be prepared, for example, by reacting a lower dialkylhydrazine with potassium cyanate to form a lower dialkyl semicarbazide which is reacted with ethyl chlorocarbonate to form a carbethoxy lower dialkyl semicarbazide, which in turn is reacted with sodium alkoxide to form the novel lower dialkyl substituted urazoles.

traction with ethyl acetate. The ethyl ace te s dis- 'tilled offend the -produet, 1,2 -diethy1 sen1iearhafnde, is

The novel trisubstituted urazole derivatives are formed by subsequently reacting a novel lower dialkyl substituted urazole with an alkylating agent such as diazomethane or a methyl halide.

The novel disubstituted urazoles, where the substituted derivative groups are not the same,- are prepared by reacting -a lower alkyl hydrazine with potassium cyanate to form a lower alkyl semicarbazide which is reacted with ethyl chlorocarbonate to form a carbethoxy'lower alkyl semicarbazide which in turn is cyclized with sodium alkoxide to form monosubstituted lower alkyl urazole. The monosubstituted lower alkyl urazole is then reacted with potassium hydroxide and an alkylatin-g agent, such as a lower dialkyl substituted sulfate, to form the desired lower dialkyl substituted urazole.

The invention is disclosed in further detail byrneans of the following examples which are set forth in the purpose of illustrating the invention, but, in no way, are to be considered as limiting the invention in spirit or scope.

EXAMPLE I 1,2-diethyl urazole To a concentrated aqueous solution containing 8.05 g. (0.05 mole) of symmetrical diethyl hydrazine dihydrochloride is added 3.45 g. (0.025 mole) of potassium carbonate in order to half neutralize the salt. To this mixture is then added a concentrated aqueous solution containing 4.05 g. (0.05 mole) of potassium cyanate. This mixture is allowed to stand over night and the product, 1,2-diethyl semicarbazide, is obtained by filtration or in the alternate by concentration before filtration or by exrecrystallized from isopropyl ether." p

Seventy-five grams (0.575 mole) ill-diethyl carbazide is mixed with 62.5 g. (0.575 mole) of ethyl chlorocarbonate and 200 inL of ethyl acetate This mixture is refluxed overnight. I The solid product, l-earhethoxy-LZ-dieth'yl semicarbazide, obtained on cooling is filtered off and washed with ether. Additional product is obtained from the filtrate by combining the filtrate and the washings and concentrating" to an oil which is taken up in ether and refiltered. The solution of product, 1- carbethoxy li diethyl semiearbazide, is then concentrated to an oil in vacuo. I

Ei hty grands (0.43 mole) of I-c'arbeth Xy-LZ-diethyI 'semica'rbazide is added to a solution of 9.07 g. 0.395

mole) of sodium and 500 ml. of ethanol. This solution refluxed for four hours after which the ethanol is distilled olf and any of the remaining ethanol is removed in vacuo. The residue is taken up in a minimum uantity of water and acidified, while cooling and stirring, with hydrochloric acid. This solution is then concentrated and extracted with ethyl acetate. The ethyl acetate solution is concentrated toasmaller volume and allowed to cool. The product, 1,2-diethylurazole, iscrystallized .out, filtered oil? and washed with a small volume of ethyl acetate. Further crops can be obtained by concentrating the ethyl acetate solutions further. The product is recrystallized from ethyl acetate and has a M.P. of -92 C. V V

Analysis.--Calcd. CeHnNgGgZ C, H, 7.1%; N, 26.7%. Found: C, 45.8%; H, 7.3%; N, 26.8%.

EXAMPLE II I,2-dz'-n-propyluraz0le The same procedure is followed as described in Exam ple 1 except that 8.75 g. (0.047 mole) of di-n-propylhydrazine dihydrochloride is substituted for' diethylhydrazine dihydrochloride. The product, di-n-propylurazole, is obtained, M.P. 91-92" C.

Analysisr- -Calcd. for C H N O C,- 51.9% H, 8.2%; N, 22.7%. Found: C, 51.7%; H, 8.4%; N, 22.4%. 7

EXAMPLE III 1,2-di-seC-bz'ltjilufd20le The same procedure as described in Example 1 is fol-- lowed except that 108.5 g. (0.382 mole) of di-sec-bntyl hydrazine dihydrochloride is substitutedfor diethylhy'drazine dihydrochloride. The product, LZ-di-Seebutymrazole, is obtained, M.P. 119-120 C.

Analysis.-Ca1cd. for cmH gNgogi C, 56.3%; H, 9.0% N, 19.7%. Found: C, 56.1%; H, 9.0%; N, 19.9%.

EXAMPLE IV 1,2-diihyl-4-mthylurazole 1 Five grams (0.032 mole) of 1,2-diethyluraz'ole, whic is the product obtained in Examplel, is added to 6.7 moles of diazomethane in ether. This mixture is allowed to'stand overnight. It is then filtered and evaporated whereupon the filtrate forms an oil, 1,2-diethyl 4 methyl ;11razole,which is distilled ,in vacuo, B.P. 86=891 C. at 1.0 mm.

Analysis-Calm;for'C H N O C, 49.1%; H, 7.7%; N, 246%. Found: C, 48.9%; H, 7.9%; N, 24.5%.

EXAMPLE V 1 ,Z-diisopropylurazole To a concentrated aqueous solution containing 16.3 g. (0.108 mole) of diisopropylhydrazine hydrochloride is added with stirring 9 g. ofpotassium cyanate which is 1 rthylial statetis refl x o e ls -i A l dp ofifigij f atbethbiiylQZ-diisopfofiYlgfseniicarbazide; obtained .on

' COoling Cafid is'filtered offjand washed with. ether. The

additional-product is obtained 1 from: theffiltrat by "c m- :biningi theTfiltnate and washings and concentrating to an ffoil which taken up' in ether andn efilteredl tu re"is thenconcentrated to an oil in -v acuo..

f Eight jgrams'f(0.43 inole) of lcarbethoxy-lli diiso- I tilled OE and any of theremainingethanol is removed in ffii'opybsemicarbazidefis added to a solutionoff907 111016) 6f S Odi UI II tIHdlSOO Of fljlGIlOl. This solution is"i'efl\iized for'four hoursafter which the ethanol The mixture "is" to" stand 6%? the 5565665 a 1.2-diisopropyl semicarhazideis extracted with ether and concentratedtosd syness;;- Q i P P7 eesaw- O0.n nl..of

is distilled offend anyof the .i'maining'lfethanolis, re 7 imoved'in yac'uolf ITheiesidue is taken up in-Ja 7 quantity of water, and acidified, while cooling'and stirring,

fwith' hydrochloric acid. This solution is then concen traded and "extracted with. ethyl acetate. 'Ihefethyl aces tatevsolution is iconcentratedi to .a smaller volume a'nd allowedfto cool. "Thefprodu'ct, l,2 -diisopropylurazole,is

crystallized out,jfil'tered 01f and-Washedwith a small by'conce'ntriating the ethylacetate solutions filrtherl 'fThe product; 1,2 diisop'ropy1urazole, ,iis recrystallized,

' The same procedure is followed asdescribed inExample V except that 43.2 -g. .(;().175 mole) of diisobutyl hydrazine hydrochloride is'substituted for diisopropyl hyn drazine hydrochloride. all ,2-diisobut'ylurazole is thereby obtained, M.-P. 115-116? C. 7'

. f l -2ediisopropyift-inetizyitlrfdzoie 1,2335 propylurazole, obtain'edfas'described infl-iiiaiinple V,1is added to 6.7fnihles'ofxdia zomethane and ether;

' This mixture is allowed to stand over night. It is filtered and evaporated whereuponthefiltrateforms an oily prod- "isrecovered; 7

not,1,2-diisopropyl-4-methylurazole;- which is distilled in vacuo.:- AnalySisL-Calcd. for C H N30 C, 54.3% H, '8,6%

I -EXAMPLB l-isopropyl-Z-ei'hylitm2ole To a cool concentrated-aqueous solution containing" 81 g. (1 mole) of potassium cyanate is added 46 o.s7s: o1'e of isopropyl s'emicarbaizide is mined with .of e'thyl acetate.

V withinthe 'scoiie ofthejappendedclaiins Y Wec'laihizy.

l sti l- 7551 .9 9) .qfis hylchlo ccash natemdzmnfl- V This 'ngixture, is refluxed overnight} "The solid. product, carbethoxyisopropylsemicarbazide} is obtained on cooling and'is filtered and washed with ether. Additional productPis obtained fromithe'filt'r'ate a by combining the filtrate an'd the washings. and concentrating to an oil which taken-11p in ether and refiltered.

The product, l-carbethoxyg lgisopropyl se'micarbazide', is

then concentrated to an oil in yacuo, 1

mole) of sodium in 500 m1. of ethanol 'lhissolution is refluxed for fsourfhoursafter which itheethanol disvacuo. The residue is'taken up'in' a quantity of water and'a'cidified, while cooling and stirring, with hydrochloric acid. This solution'is then concentrated acetate. the ethyl acetate solutions further.

Fourteen and three-tenths grams (0.077 mole) of isopropyl-urazole is dissolved in fa solution of 5.6. g."(0.1

mole), of potassium. hydroxide. 40 ml. of ethanol and a 40 ml. of water. To this solution is then added dropwise, with stirring, 15.4 g. (0.1 mole) of diethyl sulfate;

When the. addition is complete. the solution 'is refluxed "for four hours. The ethanol is the'ndistilled off and the solution concentrated in vacuo to remove water. .The

residual product, 1-isopropyl-2-ethylurazole, is extracted 'vvith laoiling alcohol and is thenconcentrated to an oil and crystallized! It is then taken up in ethyl acetate,

filtered and'the ethyl acetate distilled on. 'The residual product, '1 isopropyl 2 ethylurazole, has'a BzP off" 165C. at 2.5 mm.

Others maypractice th e*-invention in anyof'thQnu 'merous ways whiehwill be suggested by 'this 'dis'closlure to one skilledin'tde art." All such'pr'a iceo'f theinv r 7 'tion' iis' consideredjto be a pair-dis t p eaded 't 7 ans 1,2-di-sec butylurazole; 7 -I-,2-diethy1-4-1nethyhirazole? '-1,2-diiso15i'opylurazole;

1,2-diisobutylurazb1'e. I: v -1,2-diisopropyl-4 methylurazole.

1-isopropyl-2-ethylurazole.

References Cited in the file'of'thi's' patent V Nirdlinger et al.: Am. Chem. 1., vol. 43, pp.358-84' '(1940 r I Brunel et al.:

- Goodwin et al; -1 Chem. Soc.,- vol. 47 ppi 1 6 Chem. J., -vol-. 43, pp. 505453 Tsuji; Chem. Abstracts, vetfsp... e51. 12032 (1956) 

1. 1,2-DIETHYLURAZOLE.
 3. 1,2-DI-SEC-BUTYLURAZOLE. 